Previous structure-activity relationship studies indicated that a series of cocaine analogs, 3-aryltropanes with 2-diarylmethoxy substituents, selectively bind to the dopamine transporter (DAT) yet do not produce effects like those produced by cocaine. The present study compared these compounds to cocaine with respect to various effects related to the abuse liability of cocaine. All of the 2 compounds produced psychomotor stimulation assessed by increases in locomotor activity, however only the 2-(4-ClPh)PhCOCH2-3-4-Cl-Ph analog had efficacy comparable to that of cocaine. Despite nanomolar DAT affinity, only one of the 3-aryltropanes (the 2-Ph2COCH2-3-4-Cl-Ph analog) fully reproduced cocaine-like subjective effects. The majority of the compounds produced neither of these cocaine-like effects. To explore the molecular mechanisms of these drugs, their effects on DAT conformation were probed using a cysteine-accessibility assay. Previous reports indicate that cocaine binds with substantially higher affinity to DAT in outward (extracellular)- compared to inward-facing conformation, whereas atypical DAT inhibitors, such as benztropine, have more similar affinities to these conformations, and this is postulated to explain their divergent behavioral effects. All of the 2- and 2-substituted compounds tested altered cysteine accessibility of DAT in a manner similar to cocaine. Further, molecular dynamics of in silico inhibitor-DAT complexes suggested that the 2-substituted compounds reach equilibrium in the binding pocket in a cocaine-like fashion. These behavioral, biochemical and computational results show that the 3-aryltropane analogs can bind to the DAT and stabilize outward-facing DAT conformations like cocaine, yet produce effects that differ from those of cocaine. These results indicate that a simple explanation regarding the induction of inward- vs. outward-facing DAT conformation does not fully account for the atypical effects of all DAT ligands and that a more nuanced explanation, possibly involving molecular dynamics of the equilibrium of binding is necessary. The mechanisms of abused amphetamines involve the elevation of synaptic dopamine concentrations through actions at the DAT, however actions at the vesicular monoamine transporter (VMAT) are also involved. To study amphetamine function in dopamine neurons in vivo, we employed genetic and pharmacological tools in fruit flies in real-time behavioral and ex vivo whole brain optical experiments, as well as in rodents trained to self administer stimulant drugs. Novel fluorescent reporters of vesicular load and of pH revealed that, at pharmacologically relevant concentrations, amphetamine must be transported both by the plasma membrane dopamine transporter and the VMAT. The transport via VMAT causes vesicles to alkalize and redistribute their contents. Evidence collected indicates that substrate-coupled H+ antiport provides the mechanism for amphetamine induced vesicular alkalization. The importance of VMAT for AMPH action was further demonstrated in rodents trained to self administer stimulants. Routine amphetamine self administration was blocked with a novel, selective VMAT inhibitor, whereas the self administration of cocaine, which does not require actions at the VMAT for its stimulant effects, was not affected. Thus, both DAT and VMAT must work in tandem for amphetamine to produce its actions at pharmacologically relevant concentrations. Rational design of lead compounds targeting monoamine transporters (MATs) is critical to developing novel therapeutics to treat psychiatric disorders including depression and substance abuse. A 3-D dopamine transporter (DAT) computer model was used to virtually screen a commercially available small molecules library for high DAT affinity drug-like compounds. One compound (subsequently identified as Ro-25-6981, an ifenprodil analog and reputed NMDA antagonist) inhibited human dopamine, norepinephrine, and serotonin transporters in vitro. Both acute and chronic treatment in vivo induced robust, dose-dependent antidepressant-like behaviors in several rodent models with predictive validity. The compound also produced rapid antidepressant-like effects in the social-avoidance test that followed social-defeat. Chronic administration of Ro-25-6981 increased social interaction scores while improving resiliency to the mood-altering effects of stress to a greater extent than the recently discovered rapidly efficacious ketamine. Importantly, Ro-25-6981, in contrast to ketamine, exhibited minimal abuse liability in behavioral and neurological models. Ro-25-6981, a rapid-acting glutamatergic antidepressant may also functionally inhibit monoamine reuptake and produce sustained antidepressant effects in vivo. This study demonstrates, as proof of principle, the viability of using MAT computational model-based virtual screening is a viable method for identifying antidepressant lead compounds of unique scaffold. Further, the findings also suggest that combining glutamatergic and monoamine transport inhibition can produce compounds with rapid and sustained antidepressant-like effects.